Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells.
Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells.
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肿瘤坏死因子-α诱导脑胶质瘤细胞合成白介素6的机制。
DOI：
10.1186/1742-2094-7-16
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发表时间：
2010-03-06
影响因子：
9.3
通讯作者：
Kozawa O
中科院分区：
文献类型：
--
作者：
Tanabe K;Matsushima-Nishiwaki R;Yamaguchi S;Iida H;Dohi S;Kozawa O
白细胞介素（IL）-6在多种中枢神经系统功能中起关键作用，如诱导和调节反应性星形胶质细胞增生、病理性炎症反应和神经保护。肿瘤坏死因子（TNF）-α通过抑制性κ B（IκB）-核因子κ B（NFκB）通路、p38丝裂原活化蛋白（MAP）激酶和应激活化蛋白激酶（SAPK）/c-Jun N末端激酶（JNK）诱导大鼠C6胶质瘤细胞释放IL-6。本研究比以前报道的更详细地研究了TNF-α诱导IL-6释放的机制。培养的C6细胞用TNF-α刺激。采用酶联免疫吸附试验检测IL-6的释放，Western印迹法检测IκB、NFκB、MAP激酶超家族和信号转导及转录激活因子（STAT）3的磷酸化水平。实时荧光定量逆转录聚合酶链反应检测细胞内IL-6 mRNA水平。TNF-α可显著诱导NFκB B在Ser 536和Ser 468的磷酸化，但不诱导Ser 529或Ser 276的磷酸化。IκB激酶抑制剂Wedelolactone抑制TNF-α诱导的IκB磷酸化和NFκB丝氨酸536和468磷酸化。TNF-α刺激的IL-6水平升高被wedelolactone抑制。TNF-α诱导STAT 3磷酸化。Janus家族酪氨酸激酶（JAK）抑制剂I（JAK 1、2和3的抑制剂）可减弱TNF-α诱导的STAT 3磷酸化，并显著减少TNF-α刺激的IL-6释放。夹竹桃素是一种NADPH氧化酶抑制剂，可抑制细胞内活性氧，显著抑制TNF-α诱导的IL-6释放和mRNA表达。然而，夹竹桃麻素不能影响IκB、NFκB、p38 MAP激酶、SAPK/JNK或STAT 3的磷酸化。这些结果有力地表明，TNF-α通过JAK/STAT 3途径诱导C6胶质瘤细胞IL-6的合成，除了p38 MAP激酶和SAPK/JNK，NFκB B在Ser 536和Ser 468的磷酸化，以及NADPH氧化酶参与TNF-α刺激的IL-6合成。
Interleukin (IL)-6 plays a pivotal role in a variety of CNS functions such as the induction and modulation of reactive astrogliosis, pathological inflammatory responses and neuroprotection. Tumor necrosis factor (TNF)-α induces IL-6 release from rat C6 glioma cells through the inhibitory kappa B (IκB)-nuclear factor kappa B (NFκB) pathway, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). The present study investigated the mechanism of TNF-α-induced IL-6 release in more detail than has previously been reported. Cultured C6 cells were stimulated by TNF-α. IL-6 release from the cells was measured by an enzyme-linked immunosorbent assay, and the phosphorylation of IκB, NFκB, the MAP kinase superfamily, and signal transducer and activator of transcription (STAT)3 was analyzed by Western blotting. Levels of IL-6 mRNA in cells were evaluated by real-time reverse transcription-polymerase chain reaction. TNF-α significantly induced phosphorylation of NFκB at Ser 536 and Ser 468, but not at Ser 529 or Ser 276. Wedelolactone, an inhibitor of IκB kinase, suppressed both TNF-α-induced IκB phosphorylation and NFκB phosphorylation at Ser 536 and Ser 468. TNF-α-stimulated increases in IL-6 levels were suppressed by wedelolactone. TNF-α induced phosphorylation of STAT3. The Janus family of tyrosine kinase (JAK) inhibitor I, an inhibitor of JAK 1, 2 and 3, attenuated TNF-α-induced phosphorylation of STAT3 and significantly reduced TNF-α-stimulated IL-6 release. Apocynin, an inhibitor of NADPH oxidase that suppresses intracellular reactive oxygen species, significantly suppressed TNF-α-induced IL-6 release and mRNA expression. However, apocynin failed to affect the phosphorylation of IκB, NFκB, p38 MAP kinase, SAPK/JNK or STAT3. These results strongly suggest that TNF-α induces IL-6 synthesis through the JAK/STAT3 pathway in addition to p38 MAP kinase and SAPK/JNK in C6 glioma cells, and that phosphorylation of NFκB at Ser 536 and Ser 468, and NADPH oxidase are involved in TNF-α-stimulated IL-6 synthesis.
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影响因子：
4.2
作者：
Yi, Jae-Hyuk;Park, Seung-Won;Vemuganti, Raghu
通讯作者：
Vemuganti, Raghu
DOI：
10.1016/s0006-291x(02)02932-7
发表时间：
2003-01-24
影响因子：
3.1
作者：
Okazaki, T;Sakon, S;Nakano, H
通讯作者：
Nakano, H
影响因子：
5.3
作者：
Abramov, AY;Jacobson, J;Duchen, MR
通讯作者：
Duchen, MR
影响因子：
12.4
作者：
Kobori, M;Yang, Z;Yuan, J
通讯作者：
Yuan, J
影响因子：
2.9
作者：
Serrano, F;Kolluri, NS;Klann, E
通讯作者：
Klann, E